1,3-benzoxazines

ABSTRACT

New thionosalicyclic acid anilides and salts with bases are provided which have parasiticidal activity in sheep and cattle particularly against adult liver flukes in sheep and cattle and other domestic animals, especially against juvenile liver flukes. The new compounds are reaction products of poly-substituted phenols with substituted aromatic isothiocyanates, the hydrolysis products of oxo-thiono- or dithiono-dihydrobenzoxazines or the reaction products of N-phenyl-salicyl-imide chlorides with thiocompounds. Typical compounds are 3,5-dichloro-4&#39;&#39;-bromothionosalicylic acid anilide and 2-acetoxy-3,5-dichloro-N-(2&#39;&#39;methyl-4&#39;&#39;-chlorophenyl)-thionobenzamide. Novel benzoxazines obtainable from the above anilides are also provided and have similar properties Typical compounds are 3-(3&#39;&#39;,5&#39;&#39;-bistrifluoromethyl-phenyl)-6,8-dibromo-21-oxo-4 -thionodihydrobenzoxazine-(1,3), 3-(3&#39;&#39;,4&#39;&#39;-dichlorophenyl-6,8-dichloro2,4-dithiono-dihydrobenzoxazine-(1,3) and (4&#39;&#39;-bromophenyl)-6chloro-8-bromo-2,4-dithiono-dihydrobenzoxazine-(1,3). Methods for preparing a large number of both types of compounds are described. The compound are administered orally or subcutaneously in doses of 2.5 to 100 mg/kg, preferably 5 to 15 mg/kg, of body weight.

United States Patent Kurz et al.

[451 Oct. 10, 1972 [541 1,3-BENZOXAZINES [73] Assignee: Farbenfabriken Bayer Aktiengesellschaft, Leverkusen, Germany 22 Filed: March 28,1969

21 Appl.No.: 832,527

Related US. Application Data [62] Division of Ser. No. 634,835, May I, 1967,

abandoned.

[52] US. Cl ..260/244 R, 260/562, 260/479,

260/454, 260/566, 260/564, 424/248 [51] Int. Cl. ..C07d 87/00 [58] Field of Search ..260/244 R [56] References Cited UNITED STATES PATENTS 1 l/ 1967 Hasspacher ..260/244 OTHER PUBLICATIONS Yale J. Med Pharm. Chem Vol. 1 No. 2, pp. 121- 133 (1959) Primary Examiner-Henry R. Jiles Assistant Examiner--Robert T. Bond Attorney-Jacobs & Jacobs [57] ABSTRACT New thionosalicyclic acid anilides and salts with bases are provided which have parasiticidal activity in sheep and cattle particularly against adult liver flukes in sheep and cattle and other domestic animals, especially against juvenile liver flukes. The new compounds are reaction products of poly-substituted phenols with substituted aromatic isothiocyanates, the hydrolysis products of oxo-thionoor dithionodihydrobenzoxazines or the reaction products of N- phenyl-salicyl-imide chlorides with thio'compounds. Typical compounds are 3,5-dichloro-4'-bromothionosalicylic acid anilide and 2-acetoxy-3,5- dichlor0-N-(2'-methyl-4'-chlorophenyl)-thionobenzamide. Novel benzoxazines obtainable from the above anilides are also provided and have similar properties Typical compounds are 3-(3',5-bis-trifluoromethylpheny1)-6,8-dibromo-2 l -oxo-4-thiono-dihydrobenzoxazine-( 1,3 3-( 3 ',4-dichloropheny1-6,8-dichloro-2,4- dithiono-dihydrobenzoxazine-( l ,3 and (4 bromophenyl)-6-chloro-8-bromo-2,4-dithionodihydrobenzoxazine-(l,3). Methods for preparing a large number of both types of compounds are described. The compound are administered orally or subcutaneously in doses of 2.5 to 100 mg/kg, preferably 5 to 15 mg/kg, of body weight.

5 Claims, No Drawings 1 ,3-BENZOXAZINES This is a divisional of our copending application Ser. No. 634,835, filed May 1, 1967, now abandoned.

Prior Art Some thionosalicylic acid anilides substituted in the aromatic nucleus of the acid component are known. (cf. H. Rivier, S. Kunz, Helv. Chim. Acta (1932), 376; E. Schraufstatter, W. Meiser, R. Gbnnert, Z. Naturforsch. 16 b (1961), 95; G. Wagner, D. Singer, Z. Chemie 3 (1963), 146; German Pat. No. 1,045,717. These known compounds, however, are ineffective against trematodes, especially against liver flukes, for example Fasciola hepatica.

It has know been found according to the present invention that certain novel thionosalicylic acid anilides and salts thereof with suitable bases have valuable veterinary chemotherapeutic and biological parasiticidal properties. The invention also includes novel parasiticidal dihydrobenzoxazines and procedure for producing said anilides and benzoxazines;

The new thionosalicylic acid anilides of this invention have the formula:

Y R2 Rs 5 6 S 2' 3' 4 g 1' R1 NH wherein R is hydrogen or an acid radical,

R, is hydrogen, lower alkyl or lower alkoxy,

R is hydrogen, halogen, lower alkyl or lower alkoxy,

R R and R are the same or different and are each hydrogen, hydroxyl, lower alkyl, lower alkoxy, halogen, nitro, haloalkyl, alkylmercapto or acyloxand X and Y are the same or different and are each hydrogen, halogen or nitro,

with the provisos that X and Y cannot both be hydrogen at the same time and in the case where X is hydrogen Y can only be chlorine or bromine when each of R R and R is different.

A particularly valuable sub-genus of the new thionosalicylic acid anilides is those in which R in the above formula (I) is acyl, namely, compounds of the formula:

wherein R R R R R and X and Y have the same meanings set forth above and with the same provisos. Compounds in which R is acetyl, propionyl, phenylpropionyl, pivaloyl, etc., are especially active.

The new compounds of formula (I) and (11) and their salts with non-toxic inorganic or organic bases, such as sodium hydroxide and potassium hydroxide, ethanolamine, diethanolamine, piperazine, etc.,

destroy internal parasites including cestodes and trematodes and of the latter particularly the liver flukes. They are also active antibacterial, antifungal and antiprotozoan agents and have, for example, good bactericidal, nematocidal and molluscicidal effects and are active against homoand phytopathogenic fungi such as Trichophyton memagrophytes, microsporium felineum, Aspergillus niger, Penicillium commune, etc. The compounds (11) show particularly good activity against snails and worms, especially against liver flukes (Fasciola hepatica) and also against bacteria, fungi and protozoa, for example coccidia. They are administered in oral dosage forms with the usual excipients or subcutaneously in solution or suspension format dosages of 2.5 to mg/kg, preferably 5 to 15 mg/kg, of body weight depending on the particular compound being used.

The new compounds (I) are prepared by reacting a substituted phenol of the formula with a substituted aromatic isothiocyanate of the formula:

in per se known manner in the-presence of a Friedel- Crafts-catalyst, and acylating, when desired, the hydrolysis products with an acid of the formula:

. ROH (V1) The compounds (I) are also obtained by hydrolyzing, in per se known manner, .2-oxo-4-thiono-dihydrobenzoxazines( 1,3) and/or 2,4-dithiono-dihydrobenzoxazines-( 1,3) of the formula:

in which Z is oxygen or sulphur, and acylating, when desired, the hydrolysis products with an acid of the formula:

ROH v1 The hydrolysis reaction (V) of the 2-oxo-(thio-3- phenyl-4-thio-dihydrobenzoxazine-(1,3) is carried out in'a manner per se known [0. Wagner and W. Singer, Z. Chem. 3, 148 (1963) by heating a 10 percent solution in an inert, water miscible solution medium, such as dioxan, boiling between 50 and 100C at boiling temperature and introducing 1N caustic, for example,

.KOH or NaOl-l.

The compounds (I) can also be obtained by reacting an N-phenyl-salicylimide chloride of the formula:

ZQQ

with a thio compound .or alkali metal or alkaline earth metal salt thereof of the formula:

HS R (Vlll) in which R is hydrogen or an alkali metal or alkaline earth metal or a radical which can easily be detached by hydrolytic splitting of the SR -bond, such as r RB Y R2 R3 s R1 (J-NH HO-Rs R5 R4 R and'acylating, when desired, the hydrolysis products with an acid of the formula:

ROH v1 Those N-phenyl-salicylimide chlorides (VII) of the above. formula, which are not already known, can be prepared according to known types of methods by reacting the appropriately substituted salicylic acid anilide with thionyl chloride, without or with a suitable solvent, such as benzene, toluene, xylene, etc., and with or without the use of dimethylformamide as catalyst (cf. R. Gonnert, J. Johannis, E. Schraufstatter, R. Strufe, Medizin und Chemie, Verlag GmbH. Weinheim/Bergstrasse 1963, 540; U.S. Pat. No. 3,210,422). While 3-[4 -bromophenyl]-2-oxo-4-thio-6-bromodihydrobenzoxazine-(l,3) is known from the publication of G. Wagner and co-workers [Z.Chem. 3,148 (1963); Pharmazie 21,161 (1966)], the compounds of formula (V) which are used as starting materials are novel and surprisingly have like uses and activities to compounds (I) and (I1). These compounds are derivatives of 3-phenyl-2-oxo-4-thioand 3-phenyl-2,4- dithio-dihydrobenzoxazine-(1,3) and are prepared from the reaction of a compound of formula (I) or (II) with a compound of the formula:

in which Z has the above stated meaning and R and R are identical or different and denote halogen, lower alkoxy or lower alkylmercapto groups or with oxalyl (VII) chloride under liberation of 1 mol of CO and 2 mols of HCl in an inert solvent medium, such as benzol, toluol, xylol, etc. at temperatures preferably between 0C and the boiling temperature, or by reacting with P S a compound of the formula:

in which the substituents X, Y and R, R have the above stated meanings.

The invention is illustrated by thefollowing nonlimitative examples.

EXAMPLE 1 3,5 ,4'-trichloro-thionosalicylic acid anilide 14.7 Grams (0.045 mole) of N-(4-chlorophenyl)- 3,5-dichlorosalicylic acid imide chloride are dissolved in as little dioxa ne as possible. A saturated solution of 15.8 g (0.65 mole) of crystallized sodium sulphide in water is rapidly added with vigorous stirring. The mixture is stirred at room temperature fora further two hours, then poured into twice its volume of water and acidified with dilute hydrochloric acid. The precipitate is filtered off,,washed with water, dried and recrystallized from ligroin. M.p. 142C.

The following compounds are prepared in analogous manner EXAMPLE 2 From N-(2'-chloro-(4'-nitrophenyl)-5-chlorosalicylic acid imide chloride there is obtained 5,2-dichloro-4 -nitro-thionosalicylic acid anilide, mp. 148C.

EXAMPLE 3 From N-(2'-methyl-4'-nitro-5'-chlorophenyl)-5- chlorosalicylic acid imide chloride there is obtained 5,5'-dichloro-2'-methyl-4'-nitro-thionosalicylic acid anilide, m.p. 169C.

EXAMPLE 4 3 ,5 ,2 ,4',5 -pentachloro-thionosalicylic. acid anilide A-solution of 26 g (0.065 mole) of N'-(2,4',5'-

trichlorophenyl)-3,S-dichlorosalicylic acid imide chloride and 13.6 g (0.085 mole) of potassium ethyl zanthogenate in 500 ml of anhydrous acetone is heated at boiling temperature for 4 hours. The mixture is then filtered hot and the solvent removed from the filtrate in a vacuum. The residue is heated with 500 ml of a 10 percent sodium carbonate solution ona water bath for 1 hour. The mixture is then filtered and the filtrate acidified with dilute hydrochloric acid. The precipitate is filtered off, washed with water, .dried and then recrystallized from carbon tetrachloride. M.p. 183C.

The following compounds are obtained in an analogous manner EXAMPLE 5 From N-(2'-chloro-4'-nitrophenyl)-3,S-dichlorosal: icylic acid imide chloride there is obtained:

3,5,2'-trichloro-4'-nitro-thionosalicylic acid 'anilide, m.p. 160C.

EXAMPLE 6 EXAMPLE 7 From N-( 2,3 '-dichlorophenyl)-3 ,S-dichlorosalicylic acid imide chloride there is obtained:

3,5,2',3'-tetrachloro-thionosalicylic acid anilide, m.p.

EXAMPLE 8 From N-(3',5-dichlorophenyl)-3,5-dichlorosalicylic acid imide chloride there is obtained: 3,5,3',5-tetrachloro-thionosalicylic acid anilide, m.p. 131C.

EXAMPLE 9 From N-( 2 ,5 '-dichlorophenyl )-3 ,S-dichlorosalicylic acid imide chloride there is obtained:

3,5,2,5'-tetrachloro-thionosalicylic acid anilide, m.p.

EXAMPLE 10 From N-(2,3'-dichlorophenyl)-3,S-dibromosalicylic acid imide chloride there is obtained: 3,5-dibromo-2',3'-dichloro-thionosalicylic acid anilide, m.p. 150C.

EXAMPLE 1 1 From N-( 3,5-dichlorophenyl)-3,5-dibromosalicylic acid imide chloride there is obtained: 3,5-dibromo-3',5'-dichloro-thionosalicylic acid anilide,

EXAMPLE 14 3,5,2'-trichloro-thionosalicylic acid anilide 30 Grams of N-(2-chlorophenyl)-6,8-dichloro-2,4- dioxodihydrobenzoxazine-(1,3), prepared from the appropriately substituted salicylic acid anilide in analogy with the process known from Z. Chemie 3 (1963), 148, and Belgian Pat. No. 604,159, are mixed intimately with 19 g of phosphorus pentasulphide and the reaction mixture is heated at 200C for 30 minutes. The resultant mixture of N-(2'-chlorophenyl)-6,8-dich1oro 2-oxo-4-thiono-dihydrobenzoxazine-(1,3) and N-(2- chlorophenyl)-6,8-dichloro-2,4-dithionodihydrobenzoxazine-(1,3) is taken up with 400 ml of boiling dioxan and the dioxan solution is stirred at C into'400 ml of a normal potassium hydroxide solution. The mixture is then heated on a water bath for 1 hour. After cooling, the mixture is filtered and the filtrate acidified with dilute hydrochloric acid. The precipitate is filtered off, washed with water, dried and recrystallized from carbon tetrachloride. M.p. l 17C.

The following compounds are prepared in analogous manner EXAMPLE l5 3,5,2,4'-tetrachloro-thionosalicylic acid anilide, m.p. 172C.

EXAMPLE 16 3,5-dichloro-4'-methoxy-thionosalicylic acid anilide, m.p. C.

EXAMPLE 17 3,5-dich1oro-4'-ethoxy-thionosa1icylic acid anilide, m.p. 148C.

EXAMPLE 18 3,5,3-trichloro-thionosalicylic acid anilide 16.3 Grams (0.1 mole) of 2,4 dichlorophenol and 16.9 g of 3-chlorophenyl-isothiocyanate are mixed, 25 g of finely powdered aluminum chloride are added and the mixture is subsequently heated at 60C for 24 hours. After cooling, the mixture is decomposed with ice and hydrochloric acid, the supernatant water is decanted and the semi-solid residue is again treated with dilute hydrochloric acid. The mixture is then stirred with a dilute sodium hydroxide solution, filtered and the filtrate is acidified with acetic acid. The precipitate is filtered off, washed with water and recrystallized from 80 percent alcohol. M.p. 134C.

The following examples are obtained in analogous manner EXAMPLE 19 From 2,4-dichlorophenol and 3,4-dichlorophenylisothiocyanate there is obtained: 3,5,3,4-tetrachloro-thionosalicylic acid anilide, m.p. 136C.

EXAMPLE 20 and 4-bromophenylacid anilide, m.p.

analogy with the method described in Example 4 EXAMPLE 21 From N-( 3 '-chloro-4'-methyl-phenyl)-3 ,5 dichlorosalicylic acid imide chloride: 3 ,5 ,3 '-trichloro-4 '-methyl-thionosalicylic acid anilide, m.p. 138C.

EXAMPLE 22 From N-( 3 -methyl-4'-chloro-pheny1)-3 ,5- dichlorosalicylic acid imide chloride: 3 ,5 ,4 -trich1oro-3 '-methyl-thionosalicylic acid anilide m.p. 127C.

3,5-dichloro-3',4-dimethyl-thionosa1icylic acid anilide, m.p. -l40C.

EXAMPLE 24 From N-( 3 ,5 -bis-trifluoromethyl-phenyl )-3 ,5- dichlorosalicylic acid imide chloride: 3 ,5-dichloro-3 ,5'-bis-trifluoromethyl-thionosalicylic acid anilide,-m.p.; 164C.

EXAMPLE 25 From N-phenyl-3 ,5 -dichlrosalicylic acid imide chloride: 3,5-dichloro-thionosalicylic acid anilide, m.p. 136C.

EXAMPLE 26 From N-(4'-chlorophenyl)-3,5-dibromosalicylic acid .imide chloride:

3,5-dibromo-4-chloro-thionosalicylic acid anilide,

mp. 157C.

EXAMPLE 27 From N-(2,4-dichlorophenyl)-3,5-dibromosalicylic acid imide chloride: 3,5-dibromo-2',4 dichloro-thionosalicylic acid anilide, m.p. 158C EXAMPLE 28 From N-('3',4-dichlorophenyl)-3,5-dibromosalicylic acid imide chloride: 3,5-dibromo-3,4'dichloro-thionosalicylic acid anilide, m.p. 159C.

EXAMPLE 29 From N(2,4,5-trichlorophenyl)-3,S-dibromosalicylic acid imide chloride: 3,5-dibromo-2,4',5'-trichloro-thionosalicylic acid anilide, m.p. 178C.

EXAMPLE 30 From N-(2',4',6-tribromophenyl)-3,S-dibromosalicylic acid imide chloride: 3,5,2',4,6-pentabromo-thionosalicylic acid anilide, m.p. 173C.

EXAMPLE 31 From- N-(2',4,6'-trichlorophenyl)-3,5-dibromosalicylic acid imide chloride: 3,5-dibromo-2',4',6-trichloro-thionosalicylic acid anilide, m.p. 168C. 1

EXAMPLE 32 From N (2',4',6'-tribromophenyl)-3,S-dichlorosalicylic acid imide chloride: 3,5-dichloro-2,4,6-tribromo-thionosalicylic acid anilide, m.p. 164C.

EXAMPLE 33 2-acetoxy-3,5-dichloro-N-(4-chlorophenyl)- thionobenzamide 7.8 Grams (one-tenth mole) of acetyl chloride are slowly added dropwise at room temperature to a stirred solution of 33 g (one-tenth mole) 3,5,4'-trichlorothionosalicylic acid anilide and stirring is continued at room temperature for 3% hours. The precipitate is filtered off with suction, extracted several times with water and redissolved from ethanol. The 2-acetoxy-3 ,5- dichloro-N-(4'-chlorophenyl)-thionobenzamide melts at 168C.

In analogy there is obtained from 3,5,4-tribromothionosalicylic anilide and ace'tylchloride, the compound 2-acetoxy-3,5-dibromo-N-(4-bromopheny1)- thionobenzamide of m.p. 176C.

EXAMPLE 34 In analogy with Example 33 there is obtained from 3,5 ,3,4 acetyl chloride, the compound 2-acetoxy-3 ,5 dichloro-N-(3',4-dichlorophenyl)-thionobenzamide ofm.p. 188C.

EXAMPLE 35 3,5-dichloro-2l-methyl-4-chloro-thionosalicylic acid anilide A solution of 13 g of N-(2-methyl-4'-chlorophenyl- 3,5-dichlorosalicylic acid imide chloride and 5.7 g of thiourea in 200 ml of anhydrous acetone is heated at boiling temperature for 10 hours. The solvent is then distilled off and the residue is taken up with a boiling 5 percent sodium carbonate solution. The mixture is then filtered and the filtrate, after cooling, acidified with dilute hydrochloric acid. The precipitate is filtered off, washed with water, dried and recrystallized from ethanol. m.p. 180C.

EXAMPLE 36 The compound of Example 14 is also obtained in the following manner.

30 g of N"(2 ChlOl'OPhCl'lYl)e6,8-dlChl0l'O-2-OXO-4- thionodihydrobenzoxazine-(1,3) are taken up in 400 ml of boiling dioxan. The boiling solution is stirred into 400 ml of N KOH warmed to about 80C, and thereafter is heated for about 1 more hour on the waterbath. After cooling it is filtered and the filtrate acidified with dilute BC]. The precipitate is filtered off, washed with water, dried and recrystallized from carbon tetrachloride. m.p. 1 17C.

The following compounds are similarly prepared.

From N-( 2' ,4-dichlorophenyl)-6,8-dichloro-2-oxo- 4-thionodihydro-benzoxazine-( l ,3):

3 ,5 ,2 ,4 '-tetrachloro-thionosalicylic m.p. 172C.

From N-(4'-methoxyphenyl)-6,8-dichloro-2-oxo-4- acid anilide,

thionodihydro-benzoxazine-( 1,3):

3,5-dichloro-4'-methoxy-thionosalicylic acid anilide, m.p. 140C.

From N-(4-ethoxyphenyl)-6,8dichloro-2-oxo-4- thionodihydro-benzoxazine( 1,3):

3,5-dichloro-4-ethoxy-thionosalicylic acid anilide, m.p. 148C.

From N-(2,5-dichlorophenyl)-6,8-dichloro-2-oxo- 4-thionodihydro-benzoxazine-( 1 ,3): 3,5,2',5-tetrachloro-thionosalicylic acid anilide, m.pt. 196C.

From N-(4'-chlorophenyl)-6,8-dichloro-2-oxothiono-dihydrobenzoxazine-( 1.3

3,5,4'-trichloro-thionosalicylic acid anilide, m.pt. 142C.

From N-(2',4, '-trichlorophenyl)-6,8-dichloro-2- oxo-4-thiono-dihydro-benzoxazine-( 1,3

3 ,5 ,2 ,4 ,5 -pentachloro-thionosalicylic acid anilide, m.pt. 183C.

From N-( 3 ,4'-dichlorophenyl)-6,8-dichloro-2-oxo- 4-thionodihydro-benzoxazine-( 1,3 3,5,3,4'-tetrachloro-thionosalicylic acid anilide, m.pt. 136C.

From N-(4-chlorophenyl)-6,8-dichloro-2,4-dithiodihydroben2oxazine-( 1,3): 3,5,4'-trichloro-thiono-salicylic acid anilide, M.pt. 142C.

From N-( 2 -methyl-4' -chlorophenyl)-6,8-dichloro- 2,4-dithiodihydrobenzoxazine-( 1,3 3,5,4-trichloro-2-methyl-thiono-salicylic acid anilide, m.pt. 180C.

From N-(3',4-dichlorophenyl)-6,8-dichloro-2,4- dithio-dihydrobenzoxazine-(1,3):

3 ,5 ,3 ,4'-tetrachloro-thiono-salicylic M.pt. 136C.

From N-(4'-bromophenyl)-6-chloro-8-broino-2,4- dithio-dihydrobenzoxazine-( 1,3 3,4'-dibromo-5-chloro-thiono-salicylic acid anilide, m.pt. 154C.

From N-( 3 ,5 '-bistrifluoromethyl-phenyl)-6,8- dichloro-2,4-dithio-dihydrobenzoxazine-( 1,3):

3 ,5-dichloro-3 ,5 '-bis-trifluoromethyl-thiono-salicylic acid anilide. M.pt. 164C.

From N-(4-bromophenyl)-6,8-dichloro-2-oxo-4- thio-dihydrobenzoxazine-( 1,3): 3,5-dichloro-4-bromo-thionosalicylic M.pt. 164 to 165C.

From N-( 3 ,5 '-bis-trifluoromethyl-phenyl )-6,8- dichloro-2-oxo-4-thio-dihydrobenzoxazine-( 1,3 )1 3 ,5-dichloro-3 ,5 -bis-trifluoromethyl-thiono-salicylic acid anilide. M.pt. 164C.

From N-(2-methyl-4-chlorophenyl)-6,8-dichloro-2 -oxo-4-thio-dihydrobenzoxazine-(1,3): 3,5,4'-trichloro-2'methyl-thiono-salicylic acid anilide. M.pt. 180C.

From N-( 3 ,5 -bis-trifluoromethyl-phenyl)-6,8- dibromo-2-oxo-4-thio-dihydrobenzoxazine-( 1,3 3,5-dibromo-3,5-bis-trifluoromethyl-thiono-salicylic acid anilide. M.pt. 155C.

From N-(4'-chlorophenyl)-6,8-dibromo-2-oxo-4- thio-dihydrobenzoxazine-( 1,3 3,5-dibromo-4-chloro-thiono-salicy1ic acid anilide. M.pt. 157C.

From N-(4-bromophenyl)-6-chloro-8-oxo-4-thio dihydrobenzoxazine-(1,3): 3,4-dibromo-5-chloro-thiono-salicylic acid anilide. M.pt. 154C.

From N-(4-bromophenyl)-6,8-dibromo-7-methyl-2- oxo-4-thiodihydrobenzoxazine-( 1 ,3 3,5,4'-tribromo-4-methyl-thiono-salicylic acid anilide.

acid anilide.

acid anilide.

M.pt. 144C.

From N-(3,4-dichlorophenyl)-6,8-dibromo-7- methyl-2-oxo-4-thio-dihydrobenzoxazine-(1,3): 3 ,5 -dibromo-4-methyl-3 ,4 '-dichloro-thiono-salicylic acid anilide. M.pt. 173C.

From N-(3'-trifluoromethyl-phenyl)-6,8-dichloro-2- oxo-4-thio-dihydrobenzoxazine-(1,3): 3,5-dichloro-3'-trifluoromethyl-thiono-salicylic acid anilide. M.pt. 121C.

From N-(2'-trifluoromethyl-phenyl)-6,8-dichloro-2- oxo-4-thio-dihydrobenzoxazine-( 1 ,3): 3,5-dichloro-2'-trifluoromethyl-thiono-salicylic anilide. M.pt. 115C.

EXAMPLE 37 3-[4-chlorophenyl]-6,8-dichloro-2-oxo-4-thionodihydro-benzoxazine-( 1,3

To a suspension of 66.4 g (0.2 mol) of 3,5,4- trichlorothionosalicylic acid anilide in 200 ml of anhydrous toluol there are added dropwise under stirring at a temperature between 60 and C. 20 g of (0.22 mol) oxalylchloride, the resulting solution stirred at boiling temperature for a further 2 hours, the precipitate formed after cooling being suction filtered and recrystallized from dimethylformamide. M.pt. 277C.

The following compounds are similarly prepared EXAMPLE 38 From 3,5,2,5'-tetrachloro-thionosalicylic acid anilide and oxalylchloride, the compound 3-[2,5'- dichlorophenyl]-6,8-dichloro-2-oxo-4-thionodihydrobenzoxazine-(1,3). M.pt. 21 1C.

EXAMPLE 39 From 3,5,3,4'-tetrachloro-thionosalicylic acid anilide and oxalylchloride, the compound 3-[3',4- dichlorophenyl]-6,8-dichloro-2-oxo-4-thionodihydrobenzoxazine-( l ,3 M.pt. 239C.

EXAMPLE 40 From 3 ,5 ,2 ,4 ,5 -pentachloro-thionosalicylic acid acid anilide and oxalylchlon'de, the compound 3-[2',4,5'-

trichlorophenyl1-6,8-dichloro-2-oxo-4-thiono-dihYdIObCllZOXfiZillC-(l lvlpt C.

EXAMPLE 41 The following compounds are similarly prepared EXAMPLE 42 From 3,5-dibromo-3',5'-bistrifluoromethylthionosalicylic acid anilide and chloroformic acid ethyl ester, the compound 3-(3,5-bis-trifluoromethyl-phenyl)-6,8-dibromo-2-oxo-4-thionodihydrobenzoxazine- (1,3). M.pt. 210C.

EXAMPLE 43 From 3,5,4-trichloro-2'-methyl-thionosalicylic acid anilide and chloroformic acid ethyl ester, the compound 3-(2'-methyl-4'-ch1orophenyl)-6,8-dichloro-2- oxo-4-thiono-dihydrobenzoxazine-( 1,3 M.pt. 240C.

EXAMPLE 44 From 3,5-dibromo-4-chloro-thionosalicylic acid anilide and chloroformic acid methyl ester, the compound 3-(4'chlorophenyl)-6,8-dibromo-2-oxo-4- thiono-dihydrobenzoxazine-( 1,3). M.pt. 314C.

EXAMPLE 45 From 3,4-dibromo-5-chloro-thionosalicylic acid anilide and. oxalic acid chloride the compound 3-(4'- bromophenyl)-6-chlor0-8-bromo-2-oxo-4- thion0dihydrobenz0xazine-(1,3). M.pt. 299C.

EXAMPLE 46 From 3,5,4'-tribromo-4-methyl-thionosalicylic acid anilide and chloroformic acid methyl ester, the compound 3-(4'-bromophenyl)-6,8-dibromo-7-methyl-2- oxo-4-thiono-dihydrobenzoxazine-( l ,3 M.pt. 281C.

EXAMPLE 47 From 3,5-dibromo-4-methyl-3,4-dichlorothionosalicylic acid anilide and chloroformic acid methyl ester, the compound 3-(3',4'-dichl0rophenyl)- 6,8-dibromo-7-methyl-2-oxo-4-thionodihydrobenzoxazine-( 1,3). M.pt. 284C.

EXAMPLE 48 From 3,5-dichloro-3'-trifluoromethyl-thionosalicylic acid anilide and chloroformic acid methyl ester, the compound 3-(3-trifluoromethyl-phenyl)-6,8-dichloro- 2-oxo-4-thiono-dihydrobenzoxazine-( 1,3). M.pt. 215C.

EXAMPLE 49 From 3,5-dichloro2-trifluoromethyl-thionosalicylic acid. anilide and chloroformic acid methyl ester, the.

compound 3-(2'-trifluoromethyl-phenyl)-6,8-dichl0ro- 2-oxo-4-thiono-dihydrobenzoxazine-(1,3). M.pt. I 75C.

EXAMPLE 50 In similar manner to Example 41, the compound 3- (4'-bromophenyl)-6,8-dichloro-2-ox0-4-thionodihydrobenzoxazine-( 1,3) is prepared from 3,5- dichloro-4'bromo-thiosalicylic acid anilide and chloroformic acid methyl ester. M.pt. 286- 287C.

EXAMPLE 51 3-(4'-chlorophenyl)-6,8-dichloro-2,4-dithiono dihydrobenzoxazine-(1,3). M.pt. 184C.

To a stirred suspension of 32.2 g (0.1 mol) of 3,5,4'trichloro-thionosalicylic acid anilide in 250 ml of anhydrous toluol, 20.2 g (0.2 mol) of triethylamine are added and, after a clear solution has gradually formed transiently, 11.5 g (0.1 mol) of thiophosgene, diluted with some anhydrous toluol, is slowly added dropwise after the precipitation of the triethylamine salt at room temperature. Tl-lereupon it is stirred for another 20 hours at room temperature, briefly heated to the boil, suction filtered hot from insolubles, the filtrate cooled and the precipitate which falls out dissolved and allowed to crystallize from chlorobenzol.

.2 EXAMPLE 52 Similarly to Example 51, there was obtained from 3,5,4'-trichloro-2'methyl-thionosalicylic acid anilide and thiophosgene the compound 3-(2'methyl-4'- chlorophenyl)-6,8-dichloro-2,4-dithiodihydrobenzoxazine-( 1,3). Therein it is advantageous in connection with the 20 hour after-stirring at room temperature that the suction filtering be carried out cold and the volume of the filtrate be reduced one-half under vacuum. Upon crystallization from toluol the compound meltedat 190C.

EXAMPLE 5 3 Similarly to Example 52, there was obtained from 3,4'-dibromo-5-chloro-thionosalicylic acid anilide and thiophosgene the compound 3-(4'bromophenyl)-6- chloro-8-bromo-2,4-dithio-dihydrobenzoxazine-( l ,3 Upon cooling of the filtrate no appreciable amount of precipitate forms and like Example 52 the volume of the filtrate is reduced under'vacuum. Crystallized from toluol. M. pt. l9lC.

EXAMPLE 54 Similarly to Example 52, thereis obtained from 3,5 ,3'4'tetrachloro-thionosalicylic acid anilide and thiophosgene the compound 3-(3,4'-dichlorophenyl)- 6,8-dichloro-2,4-dithio dihydrobenzoxazine-( l ,3 On account of the better yield it is expedient that the residue in the filter be stirred with cold water and the insoluble part combined with the portion gained from the filtrate; Crystallized from toluol. M. pt. C.

EXAMPLE 55 Similarly to Example 51, 43.4 g.(0.l mol) of 3,5- dichloro-3,5'-bis-trifluoromethyl-thionosalicylic acid anilide were suspended in 300 ml of anhydrous toluol and, under stirring after the addition of 0.2 mol of triethylamine and 0.1 mol thiophosgene, heated to boiling under reflux for 20 hours. Thereafter it is suction filtered hot, the filtrate evaporated to dryness under vacuum and the remaining residue of the 3-(3,5'-bistrifluoromethylphenyl)-6,8-dichloro-2,4-dithiodihydrobenzoxazine-(l,3) crystallized from cyclohexane. M.pt. 152C. EXAMPLE 56 3-(4-bromophenyl)-6-chloro-8-bromo-2-oxo-4-thiodihydrobenzoxazine-( l ,3

To a stirred-suspension of 42.1 g (0.1 mol) of 3,4- dibromo-S-chloro-thionosalicylic acid anilide in 300 ml of anhydrous toluol were added at room temperature 20.2 g (0.2 mol) of triethylamine and after coming down of the triethylamine salt from the previously standing clear solution 10 g (0.1 mol) of phosgene dis solved in 50 ml of anhydrous toluolis added dropwise. After 20 hours stirring at room temperature it is heated briefly to the boil, suction filtered hot from insolubles and the precipitate deposited by the cooling of the filtrate crystallized from chlorobenzol. M.pt. 299C.

EXAMPLE 57 Similarly to Example 56, there is obtained from 3,5,4'trichloro-thionosalicylic acid anilide and phosgene in the presence of triethylamine the compound 3-(4'-chlorophenyl)-6,8-dichloro-2-oxo-4-thiodihydrobenzoxazine-( 1,3). M. pt. 277C.

EXAMPLE 58 From N-(2'-methylmercapto-4'chloro-5'-methylphenyl)-3,S-dichloro-salicylic acid imide chloride: the compound 3 ,5 ,4 '-trichloro-2' -methylmercapto-' methyl-thionosalicylic acid anilide. M. pt. 181C.

EXAMPLE 59 From N-( 2-methylmercapto4',5 dichlorophenyl 3,5-dichlorosalicylic acid imide chloride: the compound 3,5,4,5'-tetrachloro-2'-methy1mercaptothionosalicylic acid anilide: M.pt. 205C.

EXAMPLE 60 From N-(3'-trifluoromethyl-phenyl)-3,5-dichlorosalicylic acid imide chloride: the compound 3,5- dichloro-3'-trifluoromethylthionosalicylic acid anilide.

M.pt. 121C.

EXAMPLE 61 From N-(4'-bromophenyl)-3-bromo-5-chloro-salicylic acid imide chloride: the compound 3,4'-dibromo- 5-chloro-thionosalicylic acid anilide. M. pt. 154C.

EXAMPLE 62 From N-(2-trifluoromethyl-phenyl)-3,S-dichlorosalicylic acid imide chloride: the compound 3,5- dichloro-2-trifluoromethylthionosalicylic acid anilide. M.pt. l C.

EXAMPLE 63 From N-(2'-trifluoromethyl-4-bromophenyl)-3,5- dichlorosalicylic acid imide chloride: the compound 3,5-dichloro-2-trifluoromethyl-4'bromo-thionosalicylic acid anilide. M. pt. 164C.

EXAMPLE 64 From N-(3',5'-bis-trifluoromethyl-phenyl)-3,5- dibromosalicylic acid imide chloride: the compound 3 ,5-dibromo-3 ,5 -bis-trifluoromethyl-thionosalicylic acid anilide. M.pt. 155C.

EXAMPLE 65 From N-(4-bromophenyl)-3,5-dibromo-4-methylsalicylic acid imide chloride: the compound 3,5,4- tribromo-4-methyl-thionosalicylic acid anilide. M.pt. 144C.

EXAMPLE 66 .From N-(3,4'-dichlorophenyl)-3,5-dibromo-4- methylsalicylic acid imide chloride: the compound 3,5- dibromo-4-methyl-3,4-dichloro-thionosalicylic acid anilide. M. pt. 173C.

EXAMPLE 67 From N-( 3 ,4'-dichlorophenyl)-3-nitro-salicylic acid imide chloride: the compound 3-nitro-3 ',4'-dichlorothionosalicylic acid anilide. M. pt. 149C.

EXAMPLE 68 From N-(2,4,5-trichlorophenyl)-3-nitro-salicy1ic acid imide chloride: the compound 3-nitro-2,4',5'- trichloro-thionosalicylic acid anilide. M.pt. 191C.

1 EXAMPLE 69 From N-( 2-methyl-4'-chlorophenyl)-3-nitro-salicylic acid imide chloride: the compound 3-nitro-2'- methyl-4-chloro-thionosalicylic acid anilide. M. pt. 174C.

EXAMPLE 70 Similarly to Example 33 there is obtained from 3,5- dichloro-3 ,5 '-bis-trifluoromethyl-thionosalicylic acid anilide and acetylchloride the compound 2-acetoxy- 3 ,5 -dichloro-N-( 3 ,5 '-bis-trifluoromethyl-phenyl thionobenzamide. M.pt. 129C.

EXAMPLE 71 From 3,4'-dibromo-5-chloro-thionosalicylic acid anilide and acetylchloride and compound 2-acetoxy-3- bromo-5-chloro-N-(4-bromophenyl)-thionobenzamide. M.pt. 181C.

EXAMPLE 72 From 3,5-dibromo-3,5'-bis-trifluoromethylthionosalicylic acid anilide and acetylchloride the compound 2-acetoxy-3,5-dibromo-N-( 3 '5 -bistrifluoromethyl-phenyl)-thionobenzamide. M .pt. 139C.

EXAMPLE 73 tion product crystallized from toluol. M.pt. 164 to 165C.

EXAMPLE 74 3,5,4'-trichloro-3-hydroxy-thionosalicylic acid anilide 98 g (0.25 mol) of N-(3'-acetoxy-4-chlorophenyl)- 3,5-dichloro-salicylic acid imide chloride and 48 g (0.3 mol) of potassium ethyl xanthogenate were heated to boiling in 1,000 ml of dry acetone for 15 hours under stirred reflux. Thereafter it is filtered, the solvent distilled off under vacuum, the solution of the residue in 500 ml of dioxan stirred into 1,000 ml of a 1N aqueous KOH solution heated to C. and the temperature held a further one-half hour at 80C. After filtration and upon the addition of dilute HCl until reaction with Congo acid, the reaction product separates out in the form of a dark brown oil, which desirably is immediately taken up in ether. By boiling out of the evaporation residue of the ethereal solution with excess 10 percent aqueous soda solution, the reaction product can be recovered with a reduced amount of oily impurity so that upon acidification of the clarified soda solution over charcoal the desired product no longer separates out in crystalline form. Crystallization from toluol yields yellow colored crystals of m.pt. 168C.

EXAMPLE 75 Similarly to Example 74, there is obtained from N- (2-chloro-4'-acetoxy-phenyl)-3 ,S-dichlorosalicylic acid imide chloride the compound 3,5,2-trichloro-4- hydroxythionosalicylic acid anilide. M.pt. 160C.

EXAMPLE 76 EXAMPLE 77 From 3,4-dibromo-5-chloro-thionosalicylic acid anilide and B-phenylpropionylchloride there is obtained the compound 2-B-phenylpropionyloxy-3- bromo-5-chloro-N-(4'-bromo-phenyl)-thionobenzamide. M.pt. 146C.

EXAMPLE 78 From 3,4-dibromo5-chloro-thionosalicylic acid anilide and lauroylchloride there is obtained the compound 2-lauroyloxy-3-bromo-5-chloro.-N-(4-bromophenyl)-thionobenzamide. M.pt. IOOTC.

EXAMPLE 79 From 3,4'-dibromo-5-chloro-thionosalicylic acid anilide and pivaloylchloride there is obtained the compound 2-pivaloyloxy-3-bromo-5-chloro-N-(4'-bromophenyl)-thionobenzamide. M.pt. 180C.

EXAMPLE 80 From 3,4'-dibromo-5-chloro-thionosalicylic acid anilide and methanesulphonic acid chloride there is obtained the compound 2-methanesulfonyloxy-3-bromo- 5-chloro-N-(4'-bromo-phenyl)-thionobenzamide. M.pt. 206C.

EXAMPLE 81 To a suspension of 33.2 g (0.1 mol) of 3,5,4- trichlorothionosalicylic acid anilide and 1 g of sodium methylate in 200 ml of dry toluol there were added dropwise under stirring at room temperature 7.1 g (0.1 mol) of ethylisocyanate diluted with a little dry toluol and the whole thereafter heated for 8 hours under reflux. After cooling it is suction filtered and the 2-( N'- ethyl-carbaminoyloxy)-3,5-dichloro-N-(4'- chlorophenyl)-thionobenzamide is crystallized from toluol. M.pt. l63C with decomposition.

EXAMPLE 82 Similarly to Example 81, there is obtained from 3,4- dibromo-5-chloro-thionosalicylic acid anilide and ethylisocyanate the baminoyloxy)-3-bromo-5-chloro-N-(4'-bromophenyl)- thionobenzamide. M.pt. l65with decomposition.

What is claimed is:

1. A compound selected from the group consisting of a dihydrobenzoxazine derivative and its non-toxic salts, said derivative having the formula:

wherein R, is hydrogen, lower alkyl or lower alkoxy,

R is hydrogen, halogen, lower alkyl or lower alkoxy,

R R and R are each hydrogen, hydroxyl, lower alkyl, lower alkoxy, halogen, nitro, halolower-alkyl or lower alkylmercapto and X and Y are each hydrogen, halogen or nitro, with the provisos that X and Y cannot both be hydrogen and where X is hydrogen Y is only chlorine or bromine when each-of R R and R is different, and Z is oxygen or sulfur.

2. The compound of claim 1 which is 3-(4- bromophenyl)-6-chloro-8-bromo-2,4-dithionodihydrobenzoxazine-( 1 ,3).

3. The compound of claim 1 which is 3-(3',4- dichlorophenyl)-6,8-dichloro-2,4-dithionodihydrobenzoxazine-( l ,3).

4. The compound of claim 1 which is 3-(2- trifluoromethyl-phenyl)6,8-dichloro-2-oxo-4-thionocompound 2-(N'-ethyl-car-. 

2. The compound of claim 1 which is 3-(4''-bromophenyl)-6-chloro-8-bromo-2,4-dithiono-dihydrobenzoxazine-(1,3).
 3. The compound of claim 1 which is 3-(3'',4''-dichlorophenyl)-6, 8-dichloro-2,4-dithiono-dihydrobenzoxazine-(1,3).
 4. The compound of claim 1 which is 3-(2''-trifluoromethyl-phenyl)-6,8-dichloro-2-oxo-4-thiono-dihydrobenzoxazine-(1,3).
 5. The compound of claim 1 which is 3-(3'',5''-bistrifluoromethyl-phenyl)-6,8-dibromo-2-oxo-4-thiono -dihydrobenzoxazine-(1,3). 